Development of Phenothiazine-Based Theranostic Compounds That Act Both as Inhibitors of β-Amyloid Aggregation and as Imaging Probes for Amyloid Plaques in Alzheimer's Disease
Development of Phenothiazine-Based Theranostic Compounds That Act Both as Inhibitors of β-Amyloid Aggregation and as Imaging Probes for Amyloid Plaques in Alzheimer's Disease
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DOI：
10.1021/acschemneuro.6b00380
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发表时间：
2017-04-01
影响因子：
5
通讯作者：
Chen, Huixiong
中科院分区：
文献类型：
--
作者：
Dao, Pascal;Ye, Fefei;Chen, Huixiong
阿尔茨海默病(AD)的早期发现对于了解和临床治疗这一疾病以及防止其进展至关重要。专门针对大脑和视网膜中Aβ斑块的显像剂可能会导致AD的早期诊断。其中，近红外荧光(NIRF)成像已经成为临床前和早期非侵入性识别和监测疾病的一种有吸引力的工具。在本研究中，我们报道了一系列新的近红外荧光探针的设计、合成和评价。大多数探测器在PbS(>；650 nm)中显示出最大发射，这落在NIRF探测器的GOAD范围内。其中，4a1对Aβ聚集体的亲和力最高(K-d=7.5 nM)，对双转基因小鼠脑和视网膜组织切片中的Aβ斑块具有良好的靶向性。这些化合物还被发现能有效地防止Aβ纤维的形成和解聚预先形成的Aβ纤维，显示出在AD诊断和治疗中作为治疗药物的前景。
Early detection of Alzheimer's disease (AD) is imperative in enabling the understanding and clinical treatment of this disorder, as well as in preventing its progression. Imaging agents specifically targeting A beta plaques in the brain and the retina may lead to the early diagnosis of AD. Among them, near-infrared fluorescent (NIRF) imaging has emerged as an attractive tool to noninvasively identify and monitor diseases during the preclinical and early, stages. In the present study, we report the design, synthesis, and evaluation of a series of new near-infrared fluorescent probes. Most of these probes displayed maximum emission in PBS (> 650 nm), which falls in the goad range for NIRF probes. Among them, 4a1 showed the highest affinity toward A beta aggregates (K-d = 7.5 nM) and an excellent targeting ability for A beta plaques in slices of brain and retina tissue from double transgenic mice. These compounds are also found to effectively prevent A beta fibril formation and disaggregate preformed A beta fibrils, showing a promising potential as theranostic agents for the diagnosis and therapy of AD.